Spiro(cyclohexane-1,9-thioxanthenes)

ABSTRACT

4-AMINOSPIRO(CYCLOHEXANE-1,9-THIOXANTHENE) COMPOUNDS OF THE FORMULA   4-(R1-N(-R2)-),2&#39;&#39;-R3,7&#39;&#39;-R4-SPIRO(CYCLOHEXANE-1,9-   THIOXANTHENE)   WHEREIN R1 IS H OR ALKYL OF 1-6 CARBON ATOMS; R2 IS H OR ALKYL OF 1-3 CARBON ATOMS, OR, R1 AND R2 COLLECTIVELY WITH THE NITROGEN ATOM TO WHICH THEY ARE ATTACHED ARE A MORPHOLINE, PYRROLIDINE, PIPERIDINE OR PIPERAZINE RING, THE LATTER THREE CAN OPTIONALLY BE SUBSTITUTED BY A METHYL OR ETHYL GROUP; AND R3 AND R4 EACH ARE H OR CL, INCLUDING THE PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS AND QUATERNARY AMMONIUM SALTS THEREOF, HAVE PSYCHOTROPIC ACTIVITY, INCLUDING TRANQUILIZING AND THYMOANALEPTIC ACTIVITY, AND BLOOD CIRCULATORY STIMULATING, SPASMOLYTIC AND ANTIHISTAMINIC ACTIVITY.

United States Patent 3,721,672 SP[RO[CYCDOHEXANE-1,9-THIOXANI'HENES] Helmut Muller-Calgan, Richard Unger, and Hans Joachim Enenkel, Darmstadt, Germany, amignors to Merck Patent Gesellschaft mit beschrankter Haftung, Darmstadt, Germany No Drawing. Filed Nov. 13, 1970, Ser. No. 89,489 Claims priority, application Germany, Nov. 15, 1969, P 19 57 490.4 Int. Cl. A6lk 27/00; C07d 65/16, 51/66 US. Cl. 260-268 PC 27 Claims ABSTRACT OF THE DISCLOSURE 4 aminospiroIcyclohexane 1,9 thioxanthene] compounds of the formula BACKGROUND OF THE INVENTION This invention relates to novel spiro[cyclohexane-1,9'- thioxanthenes] SUMMARY OF THE INVENTION The compounds of this invention are 4-aminospiro[cyclohexane-l,9-thioxanthenes] of the general Formula I wherein R is H or alkyl of 1-6 carbon atoms; R, is H or alkyl of 1-3 carbon atoms, or, R and R collectively with the nitrogen atom to which they are attached are a morpholine, pyrrolidine, piperidine or piperazine ring, the latter three optionally substituted by methyl or e hyl; and R and R each are H or Cl, including the physiologically acceptable acid addition salts and quaternary ammonium salts thereof. These compounds have pharmacological activity, including psychotropic activity, including tranquilizing activity, and other central nervous system activity, e.g., thymoanaleptic activity, and blood circulatory stimulating, spasmolytic and antihistaminic activity.

Patented Mar. 20, 1973 DETAILED DISCUSSION Preferred compounds of Formula I are those wherein:

(1) R and R are H or alkyl as defined therein,

(2) R is H or alkyl of 1-4 carbon atoms,

(3) R; is H or alkyl of 1-3 carbon atoms,

(4) R is H, especially those as defined in (1) or (2),

(5) Both R and R are H, especially those as defined in (l) or (2),

(6) R is H and R is Cl, especially those as defined in (1) or (2), and

(7) those in physiologically acceptable acid addition salt form, preferably hydrochlorides, especially those as defined in (U-(6).

Preferred compounds of Formula I which can be pr0 duced according to this invention can be represented by the general Formula I(a):

wherein R is H or Cl, R is H or alkyl of 1-3 carbon atoms and R is H or CH or R and R together with the amino nitrogen to which they are attached represent -CH CH N(CH )CH-,;CH including the physiologically acceptable acid addition and quaternary ammonium salts thereof. Of these, especially valuable are those of the general Formula I(b) wherein R and R have the above-indicated meanings, including the physiologically acceptable acid addition salts thereof.

As stated above, R, can be H or alkyl of 1-6 carbon atoms, i.e., hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-amyl, isoamyl, Z-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, 2-methyll-butyl, tert.-arnyl, n-hexyl, isohexyl and Z-hexyl. Of these, hydrogen and alkyl of 1-4 carbon atoms, especially methyl, ethyl, propyl and isopropyl, are preferred. R; can be hydrogen or alkyl groups of l-3 carbon atoms, preferably methyl and ethyl. Additionally, R and R collectively with the nitrogen atom to which they are attached, can be heterocyclic ring, preferably morpholino, pyrrolidino, piperidino, piperazino, and pyrrolidino, piperidino, and pipcrazino substituted with a methyl or ethyl group, e.g., 2- or 3-methylpyrrolidino, Z-methylpiperidino, 4- methyl-piperidino, Z-ethylpiperidino, 4-ethylpiperidino and 4-methyl-piperazino.

R and R can be the same or difi'erent.

The compounds of Formula I can be obtained in physiologically acceptable acid addition salt form by treatment of the free base with an inorganic or organic acid whose anion does not add significantly to the toxicity thereof,

including aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monoor polybasic carboxylic, sulfonic and mineral acids. Examples of such mineral acids are hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acids, e.g., orthophosphoric acid and sulfamic acid. Examples of organic acids are formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, diethylacetic acid, oxalic acid, malonc acid, succinic acid, pimelic acid, fumaric acid, maleic acid, citric acid, gluoonic acid, lactic acid, trataric acid, malic acid, benzoic acid, salicyclic acid, phenylpropionic acid, ascorbic acid, isonitcotinic acid, nicotinic acid, methanesulfonic acid, ethane-disulfonic acid, ,e-hydroxyethanesulfonic acid, p-toluenesulfonic acid, naphthalenemonoand -disulfonic acids.

Compounds of Formula I in the form of physiologically acceptable quaternary ammonium salts can be produced by treatment of a tertiary amine of Formula I, i.e., neither R, nor R is H, with a quaternizing alkylating agent, e.g., methyl iodide, methyl bromide, dimethyl sulfate and ethyl chloride, bromide or iodide. Examples of such quaternary ammonium salts are alkyl, cycloalkyl, aralkyl, aryl and alkaryl of 1-12, preferably 1-8 carbon atoms, especially methyl, ethyl, allyl, benzyl, phenethyl, cyclopentyl, cyclohexyl, phenyl and tolyl ammonium chlorides, bromides and iodides of the compounds of Formula I, especially those of classes (1)-(6) as defined above.

Compounds of Formula I in free base form can be obtained by treatment of the corresponding acid addition salts thereof with strong base, e.g., sodium or potassium hydroxide or sodium or potassium carbonate.

The 4-aminospiro[cyclohexane-l,9'-thioxanthene] compounds of Formula I are prepared by the following reactions:

(at) A compound of the general Formula II wherein the dotted line in the 2,3-position of the cyclohexane ring represents a double bond which can be present thereat, and X. is =NOH, =NR,, (lLNR Ac or (H,NR Ac or another group convertible by reduction into the group NR R in which Ac is acyl of 1-6 carbon atoms, and Ac is acyl of 1-3 carbon atoms, or an enamine of the general Formula III /N R| \h III is treated with a reducing agent; or

(b) A compound of the general Formula IV wherein Y is Cl, Br, I or a free or reactively esterified OH, is treated with a base of the formula R R NH (V); or

(c) A compound otherwise corresponding to Formula I wherein the amino group R R N is present in a functionally modified form, is converted to a compound of Formula I by liberating the amino group by hydrogenolysis, hydrolysis, alcoholysis 0r aminolysis; or

(d) An organometallo compound of the general Formula VI M (VI) wherein M is Li or MgI-Ial, and Hal is Cl, Br or I, is treated with a hydroxylamine derivative of the formula R R NA (VII) wherein A is lower-alkoxy or Hal as defined above; or

'(e) A compound of the general Formula VIII R, R, (VIII) is reacted under intramolecular ring closure conditions with an agent forming thioether bridges; and, if desired, a thus-obtained primary (R R ='H) or secondary amine -(R,=H) of Formula I is treated with an alkylating agent; and/or a compound of the general Formula I in free base form is converted, by treatment with an acid or with a quaternization agent, respectively, into a physiologically acceptable acid addition or quaternary ammonium salt, respectively; or a compound of the general Formula I in salt form is converted to the corresponding free base.

When X in Formula II is (H,NR-,,Ac,), Ac can be any acyl group which can be reduced to an alkyl group of up to 6 carbon atoms, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and capronyl. When X in compounds of Formula II is (H,NR,Ac Ac can be formyl, acetyl or propionyl group.

X can also be any other group which can be converted reductively into the group NR R for example,

as =Nmmma1 wherein R represents a lower alkylidene group of up to 6 carbon atoms, preferably methylene, ethylene, propylidene, isopropylidene, l-butylidene, or Z-butylidene.

In the compounds of Formula IV, Y can be an optionally reactively esterified hydroxyl group, e.g., alkyl-, aralkyl-, and aryl-sulfonyloxy groups of the general formula OSO R wherein R is, for example, methyl, ethyl, propyl, isopropyl, n-butyl, benzyl, phenyl, 0-, m-, and p-tolyl and naphthyl, preferably those containing up to 10 carbon atoms, especially methyl or p-tolyl. When Y=Hal, Hal is preferably Cl.

Examples of the compounds of Formula VII wherein A is lower-alkoxy of 1-4 carbon atoms, are preferably methoxy and ethoxy and also propoxy, isopropoxy, n-

butoxy and isobutoxy. Among the haloamines of Formula VII, i.e., A is Hal, the chloroamines are preferred.

The amines of Formula I preferably are prepared by the reduction of compounds of Formulae II and III.

Of the starting compounds of Formula II, the oximes are preferred, i.e., X is N=OH, e.g., spiroIcyclohexanel,9-thioxanthenel 4 oxime and spiro[cyclohexene-(2)- l,9-thioxanthenel-4-oxime and the corresponding 2'- chloroor 2',7'-dichloro compounds.

Further compounds of Formulae II and [II which can be reduced in accordance with this invention are imines, e.g., 4-iminospiro[cyclohexane-l,9'-thioxanthene] and 4- iminospiro[cyclohexene-(Z) 1,9 thioxanthene] and the corresponding N-alkyl compounds, e.g., 4-methylimino-, 4-ethylimino-, 4 propylimino-, 4-isopropylimino-, 4-nbutylimino-, 4-isobutylimino-, 4-sec.butylimino-, 4-tert.- butylimino-, 4-n-amylimino-, 4-isoamylimino-, 4-pentyl- (2)-imino-, 4-pentyl-(3)-imino-, 4-neopentylimino-, 4- [3 methylbutyl (2)]imino-, 4-[2-methylbutyl-(l)] imino-, 4-tert.-amylimin0-, 4-n-hexylimino-, 4-isohexylimino and 4 hexyl-(Z)-iminospiro[cyclohexane 1,9- thioxanthene] and spiro[cyclohexene-(2)-l,9'-thioxanthene], respectively; and the corresponding acyl compounds, e.g., 4-formamido-, 4-acetamid0-, 4-propionamido-, 4-butylamido-, 4-isobutylamino-, 4-valeramido-, 4-isovaleramido-, 4-capronamido-, 4 N methylforrnamido-, 4-N-methylacetamido, 4-N-methylpropionamido-, 4-N-ethylformamido-, 4-N-ethylacetamido-, 4-N-isopropylformamido-, 4-N-isopropylbutyramido-, 4-N-n-butylacetamido-spiro[cyclohexene 1.9 thioxanthene] and spiro[cyclohexene-(2)-l,9'-thioxanthene], respectively.

Examples of the enamines of Formula III are 4-dimethylamino-, 4-diethylamino-, 4-methylethylamino-, 4-methylpropylamino-, 4-methylisopropylamino-, 4-methylbutylamino-, 4 ethylbutylamiuo-, 4 methylisobutylamino-, methyl-sec.-butylamino-, 4 methyl-tert.-butylamino-, 4- methyl-n-amylamino-, 4-methylisoamylamino-, 4-methylpentyl-(2)-amino-, 4-methylpentyl-(3)-amino-, 4-methylneopentylamino-, 4 methyl-[3-methylbutyl-(2)]-amino-, 4 methy1-[2-methylbuty1-(l)]-amino-, 4 methyl-ternamylamino-, 4-methyl-n-hexylamino-, 4 methylisohexylamino-, 4 methyIhexyl-(2)-amino-, 4 pyrrolidino-, 4- piperidino-, 4-piperazino-, 4-morpholino-, 4-(4-methylpiperazino)-, 4-(2-methylpyrrolidino)-, 4-(3-methylpyrrolidino)-, 4-(2-methylpiperidino)-, 4 (2 ethylpiperidino)-, 4-(4-methy1piperidino)- and 4-(4-ethylpiperidino)- spiro[cyclohexene-(3)-l,9-thioxanthene], as well as the corresponding 2,4-di-unsaturated compounds of the cyclohexane ring, including those which are monoor disubstituted by chlorine in the 2'- and/or 7-position of the thioxanthene system.

A compound of Formula II or III can be reduced to a compound of Formula I, for example, by catalytic hydrogenation. Suitable catalysts for this purpose are the conventional ones, preferably a noble metal catalyst. Copper-chromium oxide catalysts and nickel and cobalt catalysts can also be employed. Examples of the noble metal catalysts which can be employed, are, for example, supported catalysts, e.g., palladium on charcoal, oxide catalysts, e.g., platinum oxide and finely divided metal catalysts, e.g., platinum black. Nickel and cobalt catalysts are suitably utilized as Raney metals. Nickel on kieselguhr or pumice as the support can also be employed. The hydrogenation is conducted under normal pressure and at room temperature, or under elevated pressure (up to about 200 atmospheres) and/or elevated temperature (up to about 200 C.).

The hydrogenation is suitably conducted in the presence of a solvent, preferably methanol, ethanol, isopropanol, tert.-butanol, ethyl acetate, dioxane, tetrahydrofuran, water, acetic acid, an aqueous mineral acid, or alkali solution, or mixtures of the above-mentioned solvents, taking into consideration the nature of the starting compound. Thus, although it is basically possible to operate in the acidic, neutral, or alkaline range, with com- 6 pounds of Formula II which contain C=N double bond, reduction in a neutral or basic medium is preferred.

The reduction can also be acccomplished with nascent hydrogen produced, for example, by treating metals with acids or bases. Thus, for example, zinc in an acid or an alkaline solution, iron in hydrochloric acid or acetic acid, or tin in hydrochloric acid can be employed. Likewise suitable is the use of sodium or another alkali metal in ethanol, isopropanol or butanol. Furthermore, it is possible to employ an aluminum-nickel alloy in an alkalineaqueous solution, optionally with the addition of ethanol. Also sodium amalgam or aluminum amalgam in an aqueous-alcoholic or aqueous solution is suitable for the production of nascent hydrogen. The reaction can also be conducted in a heterogeneous phase, preferably employing an aqueous phase and a benzene or toluene phase. The reaction temperatures used in this process range between room temperature and the boiling point of the solvent employed. Advantageously, the reaction is terminated by boiling the reaction mixture.

Starting compounds of Formula II can also be converted, according to this invention, into amines of Formula I by cathodic reduction. For this purpose, an aqueous-acidic reaction solution is employed which optionally contains another solvent, e.g., glacial acetic acid or ethanol, and the reduction is conducted on a lead, copper, nickel or carbon electrode.

Other reducing agents which can be employed are complex metal hydrides, preferably, for example, lithium aluminum hydride and sodium borohydride, optionally in the presence of a Lewis acid, e.g., aluminum chloride or lithium bromide, and diborane, which can be prepared in situ from boron trifluoride etherate and NaBH Especially suitable starting materials for this reducing method are Schitf bases of Formula II (X is =NR Others are the acylamines of Formula [I [X is (H,NR Ac or Complex metal hydrides are especially suitable for the reduction of 2'-chloroand 2',7"dichloro-substituted starting compounds. The reaction is advantageously conducted in the presence of an inert solvent, e.g., ether, tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether. When reducing with sodium borohydride, the reaction can, for example, be carried out in water, aqueous alcohol, or acetonitrile. The reaction is advantageously conducted at room temperature or cooling with ice and can be terminated by boiling the reaction mixture. The required reaction time is usually at least /2 hour. The reaction mixture often is allowed to boil for a longer period of time, e.g., 12 hours, in order to complete the reaction. The thusformed metal complexes can be decomposed, for example, with water and/or a dilute aqueous acid, e.g., hydrochloric or sulfuric acid, or with an aqueous ammonium chloride solution.

The amines of Formula I can also be produced from the 4-imino-compounds of Formula II (X is =NR and R is H) by reduction with formic acid or with corresponding ammonium formates or formamides. In this reaction, in place of the less accessible imines, the 4-ketospiro[cyclohexane (or cyclohexene)-l,9'-thioxanthene] compounds can be employed and converted in situ into the required 4-imino compounds by the Leuckart-Wallach reaction, under conditions disclosed in the literature, in the presence of amines and formic acid or derivatives thereof. The further processing of the reaction mixture is thereafter conducted in the same reaction solution without isolation of the imine.

Basically, all methods described in the literature can be utilized for the reduction reaction of this invention, the selected one depending on which of the above-mentioned starting materials is chosen.

Any double bonds in the 2,3-position of the spiro [cyclohexene-l,9'-thioxanthene] residue which may be present in the starting compounds can be hydrogenated simul taneously with the main reaction, e.g., reduction of an oxime or a Schitf base of Formula II (X is :NOH or =NR or subsequently thereto, e.g., when reducing with LiAlI-I or NaBH -If chloro-substituents are present in the thioxanthene ring of the starting compounds I], they can, if desired, be split off, during the reduction with nascent hydrogen or during the catalytic hydrogenation. However, if the chloro-substituent or -substituents is to be retained, it is more advantageous according to the invention to conduct the reduction with a complex metal hydride, e.g., LiAlI-h, or diborane, since aromatically bound chloro-groups are normally not attacked by these reagents.

According to this invention, it is also possible to obtain the compounds I by reacting compounds of Formula IV with a base of Formula V or an agent which evolves such a base under the reaction conditions. Suitable starting compounds of Formula IV are: 4-hydroxyspiro[cyclohexane-l,9'-thioxanthcne] and the derivatives thereof having a reactively esterified 4-hydroxy group, e.g., a sulfonyloxy group, preferably A-ptoluene-sulfonyloxyand 4-methanesulfonyloxyspiro[cyclohexane 1,9 thioxanthene], 4-chloro-, 4-bromo-, and 4-iodospiro[cyclo hexane-l,9'-thioxanthene], and the corresponding compounds unsaturated in the 2,3-psition of the cyclohexane ring, unsubstituted, or monoor disubstituted in the 2'- and/or 7-position of the thioxanthene system by chlorine.

Preferred bases of Formula V are: ammonia, methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec.-butyl-, tert.-butyl-, dimethyl-, diethyl-, methylethyl-, methylpropyl-, methylisopropyl-, methylbutyl-, methylisobutyl-, methyl-sec.-butyl-, methyl-terL-butyl-amine, pyrrolidine, piperidine, morpholine, 4-methyland 4-ethyl-piperazine, Lmethyland S-ethyl-pyrrolidine, 2- or 4-methyland 2- ethyl-piperidine. Others are n-amyl-, isoamyl-, 2-pentyl-, 3-pentyl-, neopentyl-, 3-methylbutyl-(2)-, tert.-amyl-, 2- methylbutyl-(l)-, nhexyl-, isohexyl-, 2-hexyl-, methyl-namy1-, methylisoamyl-, methylpentyl-(2)-, methylpentyl- (3)-, methylneopentyl-, methyl-[3 methylbutyl-(2)1-, methyl-[2-methylbutyl-(l)]-, methyl-tert.-amyl-, methyln-hexyl-, methylisohexyl-, and methylhexyl-(Zhamine.

Agents evolving a base in situ are, in addition to hexamethylene-tetramine, the easily decomposed salts of the bases V, e.g., the carbonates, bicarbonates or carbaminates.

The reaction of IV with V can be conducted in the presence or absence of a solvent. Examples of suitable solvents are the lower aliphatic alcohols, e.g., methanol, ethanol and isopropanol, the lower aliphatic ketones, e.g., acetone, methyl ethyl ketone, cyclohexanone and butanone, aromatic hydrocarbons, e.g., benzene and toluene, acetonitrile, or mixtures thereof, can be employed as the solvent. When selecting the solvent, it is, of course, necessary to consider the structure of the starting compounds. For example, with compounds IV wherein Y=OI-I, the use of alcohols as the solvent is less advantageous, due to the possibility of side reactions. Depending on the constitution of the starting compounds, the reaction is conducted at temperatures of between 0 and about 200 (3., preferably between room temperature and the boiling point of the solvent employed.

It is also possible to conduct the reaction using an excess of the base V as the reaction solvent. The reaction can be accelerated by conducting it under pressure and/or at an elevated temperature. In an especially advantageous mode of operation when employing alcohols (IV, Y=OH) as the starting compounds in this process, catalysts are preferably added, e.g., Raney nickel, platinum, or palladium, and the reaction mixture is heated in a pressure vessel, preferably to 130-220 C. For this reaction, methods set forth in the literature can be utilized.

Compounds of Formula I can also be prepared by liberating the amino group of a compound otherwise corresponding to Formula I, whose amino group is pres- 8 ent in a functionally modified form, by hydrogenolysis, hydrolysis, alcoholysis or aminolysis.

Examples of functionally modified amino groups are acylated amino groups and N-arylsulfonyl, Nbenzal, N- benzyl, N-carbobenzoxy, or N-nitrosoamines. For example, starting compounds which can be employed are: 4-formamido-, 4-acetamido-, 4-propionamido, 4-benzamido-, 4-trichloroacetamido-, 4 phthalimido-, 4-benzenesulfonamido-, 4-methanesulfonamido-, 4-p-toluenesulfonamido-, 4-benzylidenamino-, 4-benzylamino-, 4 carbobenzoxyamino-, and 4-nitrosoamino-spiro[cyclohcxanel,9'-thioxanthene], and corresponding compounds unsaturated in the 2,3-position of the cyclohexane ring, and compounds corresponding to each which are monoor disubstituted by chlorine in the 2- and/or 7'-position.

The amino group can be in the form of an isocyanate group. For example, spiro[cyclohexane-l,9'-thioxanthen]- yl-4-isocyanates can be produced as intermediates in a Hofmann, Curtius, Lossen or Schmidt degradation of spiro[cyclohexane-1,9'-thioxanthene] 4 carboxylic acid amides.

A hydrogenolysis is conducted with catalytically activated hydrogen under the conditions described above. A hydrolysis can be conducted in an acidic or alkaline medium, e.g., in an aqueous-alcoholic medium, at temperatures of between 0 and preferably l00 C. Preferred acids are hydrochloric acid and/or sulfuric acid. Preferred bases are sodium or potassium hydroxide or carbonate.

The amino group of an acylated amino derivative of an amine of Formula I can be liberated by alcoholysis, by treatment with a lower aliphatic alcohol in the presence of hydrogen chloride or an alkali or alkaline earth metal alcoholate, at temperatures of between 0 C. and the boiling temperature. The amino group can also be liberated by aminolysis, e.g., by treating the starting amide in an autoclave with ammonia or an amine, e.g., methylor ethylamine. The amine or ammonia employed in this connecton also serves as the solvent when employed in a large excess. The reaction is conducted at reaction temperatures of up to about 250 C. Other methods described in the literature can likewise be employed to split the acylamines. Thus, it is possible, for example, to split 4-phthalimidospiro[cyclohexane 1,9 thioxanthene] derivatives and the corresponding 2-cyclohexenes to produce the corresponding amines by reaction with hydrazine or phenylhydrazine (hydrozinolysis). The reaction conditions are relatively mild. Thus, boiling the alcoholic reaction solution containing hydrazine hydrate during a few hours frequently is sufiicient. Optionally, the reaction can also be conducted by allowing the reaction mixture to stand for a longer period of time at room temperature. The reaction mixture is worked up, when employing hydrazine, in the presence of a mineral acid, preferably hydrochloric acid. When using phenylhydrazines, the desired amine is, however, obtained directly.

The compounds I of this invention can also be prepared by reacting organometallic compounds of Formula VI with hydroxylamine derivatives of Formula VII. Organometallic compounds which are preferably employed are spiro[cyclohexane-l,9'-thioxanthene]-4-lithium; spiro[cyclohexane-l,9'-thioxanthene]-4-magnesium chloride, bromide or iodide; and the corresponding compounds monoor disubstituted by chlorine in the 2'- and/or 7'-position of the thioxanthene system. These organometallic compounds can be obtained in a conventional manner from the corresponding spiro[cyclohexane-l,9'-thioxanthene]-4- halides. Preferred hydroxylamine derivatives are 0- methyland O-ethylhydroxylamine, as well as chloroamine. The above-mentioned reactions are conducted under the conditions described in the literature. Preferred are low temperatures, e.g., between -20 C. and room temperature, employing reaction times of between a few minutes and 2 hours.

Suitable intramolecular ring closing agents forming thioether bridges are sulfur chlorides, e.g., sulfur dichloride, sulfur monochloride and thionyl chloride. Also, elemental sulfur and agents splitting ofi' sulfur under the reaction conditions, such as, for example, sulfides, polysulfides or thiosulfates can be used. The use of catalysts of the Friedel-Crafts type is advantageous, e.g., aluminum chloride, boron trifluoride, lithium bromide, iron (III) chloride and zinc chloride and etherates or alcoholates of these compounds. The reaction can also be conducted with other catalysts, e.g., copper, or in the absence of a catalyst. In case sulfur or an agent splitting off sulfur is employed as the reagent, the reaction is preferably conducted in the absence of a solvent, advantageously in the melt, at temperatures between about 50 and 250 C. In contrast thereto, when employing sulfur chlorides, it is advantageous to operate in the presence of an inert solvent, e.g., carbon disulfide, at temperatures of between about -20 C. and 100 C. Reaction times range between about )6 hour and 24 hours.

Subsequently to the synthesis of a primary, secondary or tertiary amine I of this invention, the thus-obtained products can be alkylated with alkylating agents in order to obtain secondary and tertiary amines of Formula I and quaternary ammonium salts thereof, respectively.

Preferred alkylating agents are alkyl esters of inorganic acids, e.g., hydrohalic acids, sulfuric acid, and phosphoric acid or organic sulfonic acids, e.g., p-toluenesulfonic acid. The reaction can also advantageously be conducted in two stages, by first condensing with aldehydes or ketones, to form aldehyde ammonias or Schiff bases, alkylating the latter with an alkylating agent, and hydrolyzing the product. For example, a primary amine of Formula I (R, and R =H) can be condensed with an aromatic aldehyde, preferably benzaldehyde, and the condensation product can then be treated with an alkyl halide, e.g., methyl chloride, methyl bromide, methyl iodide, ethyl bromide, isopropyl bromide, or dimethyl sulfate. In this step, the quaternary salt of the Schiif base is first produced, which is then converted into the secondary amine, with the aldehyde being split off, for example by treatment with aqueous ethanol or with an acid, e.g., hydrochloric acid. Furthermore, a secondary amine of Formula I (R =H) can be reacted with an aldehyde in the presence of formic acid or with an alcohol in the presence of catalysts, such as Raney nickel. Generally, the methods set forth in the literature for the alkylation of primary or secondary amines can be employed.

The novel compounds can be employed in a mixture with solid, liquid, and/or semisolid excipients in the human or veterinary medicine. Vehicles for this purpose are organic or inorganic carriers suitable for parenteral or enteral application and which do not react with the active compound, such as, for example, water, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol, etc. Especially suitable for parenteral application are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants. Suitable for enteral application are tablets, dragees, syrups and juices. The above-mentioned preparations can be sterilized or mixed with auxiliary substances, such as preservatives, stabilizers, or wetting agents, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatous substances.

The novel compounds can be administered parenterally or enterally in dosages of from 2 to 100 mg., preferably 5 to 80 mg., per dosage unit, preferably in admixture with 1-5,000 mg, preferably 5 to 500 mg., of a pharmaceutical carrier.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Temperatures are in degrees centigrade.

Starting compounds of Formulae 11 through VlII are, in part, conventional and can be produced, in part, in accordance with methods described in the literature, as follows:

Cyanoethylation of thioxanthene sulfoxide in the presence of benzyltrimethylammonium hydroxide produces bis(2-cyanoethy1)thioxanthene sulfoxide (M.P. 198 C.), which latter compound is reduced with triphenylphosphine to 9,9-bis(2-cyanoethyl)thioxanthene. Hydrolysis yields 9,9-thioxanthene-dipropionic acid (M.P. 202203 C.), the dimethyl ester (M.P. 97-98 C.) of which is cyclized in the presence of sodium methylate to spiro[cyclohexane 1,9 thioxanthen1-4-one 3 carboxylic acid methyl ester (M.P. 192-193 C.). Saponification and decarboxylation produces spiro[cyclohexane-1,9'-thioxanthen]-4-one (M.P. 148 C.). Analogously, the remaining ketones of Formula II (X=O) are obtained from 2- chloroor 2,7-dichlorothioxanthene, by way of the corresponding sulfoxides. The ketones can be reduced (preferably by catalytic hydrogenation) to the corresponding cyclohexanols (IV, Y=OH), are converted, with hydroxylamine, into the oximes (II, X=NO1-l) or, with amines, into the Schilf bases (II, X=NR,), or into the enamines (III). The alcohols (IV, Y=OH) are converted to the corresponding sulfonic acid esters when reacted with ptoluenesulfonic acid chloride or methanesulfonic acid chloride. By reaction with hydrogen chloride or bromide, phosphorus tribromide, thionyl chloride, or other inorganic acid halogenides, the corresponding 4-halo-compounds are produced. From these, the corresponding organometallic compounds (VI) are prepared with magnesium or lithium. The 4-phthalimidospiro[cyclohexanel,9'-thioxanthenes] are obtained with potassium phthulimide.

Spiro[cyclohexene 1,9 thioxanthen]-4-one and the corresponding monoor disubstituted 2- and/or 7'- chloro-substituted compounds are obtained from 9-formylthioxanthenes by condensation with methyl vinyl ketone.

The starting materials can also be formed in situ. For example, the Schiff bases (ll, X=NR can be produced by heating a 4 ketospiro[cyclohexane 1,9 thioxanthene] of Formula II with primary amines in an autoclave, preferably to 150-250 C. These Schiff bases are then hydrogenated to the corresponding amines I in the same vessel without isolation, after the addition of a catalyst.

Example 1 (a) 58 g. of crude spiro[cyclohexane 1,9 thioxanthen1-4-one-oxime (obtained from the ketone and bydroxylamine) is dissolved in 1.3 l. of boiling butanol. To this reaction mixture is added 69 g. of metallic so dium, in incremental portions, and the mixture is boiled until the sodium is dissolved. Thereafter, the butanol is distilled off, the residue taken up in water and extracted with ether. The ether phase is dried with sodium sulfate, and 4-aminospiro[cyclohexane 1,9 thioxanthene] hydrochloride is precipitated with ethereal hydrochloric acid; M.P. 310 (from ethanol/ether).

(b) 13.7 g. of 4-aminospiroicyclohexane 1,9 thioxanthene] and 2.6 g. of formic acid are dissolved in 250 ml. of toluene and boiled for 2 hours with the use of a reflux condenser. The reaction mixture is allowed to boil for another 2 hours, utilizing a water trap. Thereafter, another 2.6 g. of formic acid is added, and the reaction mixture is boiled for 2 hours under reflux condensation and another 12 hours with the use of a water trap. By concentration of the reaction mixture, 4-formylamino spiro[cyclohexane 1,9 thioxanthene] is obtained, MI. 208. The formyl compound is dissolved in ml. of absolute tetrahydrofuran and added dropwise to 3.2 g. of lithium aluminum hydride in ml. of absolute tetrahydrofuran. The reaction mixture is boiled for about 6 hours, allowed to cool, and, under agitation, dilute hydrochloric acid is added dropwise. Then, the largest portion of the tetrahydrofuran is distilled off and washed with ether. Subsequently, the acidic aqueous phase is mixed with tartaric acid, stirred into an excess of solution of sodium hydroxide, and extracted with chloroform. After the dried chloroform has been distilled off, 4- methylaminospiro[cyclohexane 1,9 thioxanthene] is obtained; hydrochloride, M.P. 279.

(c) 12.3 g. of 4-methylaminospiro[cyclohexane-1,9- thioxanthene] is converted, by boiling with formic acid in toluene, analogously to Example 1(b), into 4-methylformylaminospiro[cyc1ohexane l,9'-thioxanthene] (MP. 172'); the latter compound is then reduced, with 3.2 g. of lithium aluminum hydride, to 4 dimethylarninospiro- [cyclohexane 1,9 thioxanthene]; hydrochloride, M.P. 270.

(d) 3.8 g. of 4 aminospiro[cyclohexane 1,9 thioxanthene] hydrochloride is heated with 40 ml. of formic acid, 0.92 g. of sodium formate and ml. of 35% formaldehyde solution for 3 hours to 60 and then for 2 hours to 100. Thereafter, the formic acid is distilled off, the residue is taken up in dilute solution of sodium hydroxide, extracted with ether, and, from the dried ether extract, 4 dimethylaminospiro[cyclohexane 1,9- thioxanthene] is obtained; hydrochloride, MP. 270".

(e) A solution of 5 g. of 4 aminospiro[cyclohexane- 1,9 thioxanthene] in 50 ml. of benzene is boiled on a water trap for about 2 hours with 3 g. of benzaldehyde. The thus-obtained benzene solution of the Schiff base is shaken, together with g. of methyl iodide, for 12 hours at 150 in a bomb tube, and then the benzene and the excess methyl iodide are distilled off. The residue is boiled for 10 minutes in 90% ethanol, the alcohol is distilled off, the reaction mixture taken up in dilute hydrochloric acid, and the thus split-off benzaldehyde is extracted with ether. The acidic aqueous solution is rendered alkaline with solution of sodium hydroxide and extracted with chloroform. After the chloroform solution has been dried and evaporated, one obtains 4-methylaminospiro[cyclohexane 1,9 thioxanthene]; hydrochloride, M.P. 279.

(f) 4.22 g. of 4 aminospirolcyclohexane 1,9 thioxanthene] and 0.96 g. of bis(2-ch1oroethyl)methylamine hydrochloride are boiled for 12 hours in a mixture of 80 ml. of acetonitrile and 110 ml. of ethanol. Thereafter, the solvent mixture is distilled 01f, the residue is taken up in dilute solution of sodium hydroxide and chloroform, and the chloroform extract is chromatographed on silica gel. With benzene/diethylamine (9:1), 4 (4 methylpiperazino)-spiro[cyc1ohexane 1,9 thioxanthene] is obtained; dihydrochloride, MP. 287; dihydrobromide, MP. 300.

Analogously, by reaction with bis(2-ch1oroethyl) ether, 1,4-dichlorobutane,

1,5-dichloropentane, bis(2-chloroethyl)amine hydrochloride,

1 ,4-dichloropentane, 1,4-dichloro-2-methylbutane, 1,5-dichlorohexane, and

his Z-chloroethyl ethylamine hydrochloride,

the following compounds are obtained, respectively:

4-morpholinospiro[cyclohexane-1,9'-thioxanthene] hydrochloride;

4-pyrro1idinospiro[cyclohexane- 1 ,9'-thioxanthene] hydrochloride;

4-piperidinospiro [cyclohexane-l,9'-thioxanthene] hydrobromide;

4-piperazinospiro[cyclohexane-1,9'-thioxanthene] dihydrobromide;

4- 2-methylpyrrolidino)-spiro[cyclohexane-1,9'-

thioxanthene] hydrochloride;

12 4- B-methylpyrrolidino)-spiro[cyclohexane-l ,9'-

thioxanthene] hydrochloride; 4-(2-methylpiperidino)-spiro[cyclohexane-l,9'-

thioxanthene] hydrobromide; and 4- 4-ethyl pi perazino)-spiro [cyclohexane- 1 ,9'-

thioxanthene] dihydrochloride.

(g) 3 g. of 4 dimethylaminospiro[cyclohexane 1,9- thioxanthene] is dissolved in 30 ml. of acetonitrile and shaken in a bomb tube with 3 g. of methyl bromide for 12 hours at Thereafter, the reaction mixture is diluted with ether and vacuum-filtered, thus obtained N, N,N trimethyl-N-spiro[cyclohexane 1,9 thioxanthen] yl-(4)-ammonium bromide, M.P. 245246.

Example 2 78 g. of crude spiro[cyclohexane 1,9 thioxanthenl- 4-one oxime is dissolved in a mixture of 300 ml. of methanol, 300 m1. of tetrahydrofuran and 530 ml. of 0.5 N methanolic KOH. After adding 50 g. of Raney nickel, moistened with methanol, the hydrogenation is conducted at 6 atmospheres and 55. After about 5 hours, the hydrogenation is terminated. The reaction mixture is vacuum filtered from the catalyst, the solvent mixture is distilled off, and the reaction mixture is taken up in water and extracted with chloroform, whereafter it is concentrated by evaporation, taken up in a small amount of ethanol, and 4-aminospiro[cyclohexane 1,9 thioxanthene] hydrochloride is precipitated with ethered hydrochloric acid, MP. 310".

Example 3 11.4 g. of crude spiro[cyclohexene-(2)-1,9thioxanthen]-4-0ne oxime (obtainable from 9-formylthioxanthene [M.P. 101"] by condensation with methyl vinyl ketone and reaction of the thus-formed spiro[cyc1ohexene-(2)- l,9'-thioxanthen]-4-one with hydroxylamine hydrochloride) is hydrogenated in the presence of Raney nickel analogously to Example 1(a). After absorbing an amount of hydrogen corresponding to 3 mols and conducting the usual working-up steps, 4 aminospiro[cyclohexane-1,9- thioxanthene] hydrochloride is obtained, MP. 310.

Example 4 (a) 20 g. of spiro[cyclohexane-l,9-thioxanthen]-4-one is melted, with 30 g. of isopropylamine, in a bomb tube and heated for 18 hours to 200. Then the excess isopropylamine is removed by distillation, the crude residue of 4 n isopropyliminospiro[cyclohexanel,9-thioxanthene] is dissolved in 250 ml. of absolute tetrahydrofuran. and this solution is added dropwise to 5 g. of lithium aluminum hydride in ml. of absolute tetrahydrofuran. Thereafter, the mixture is boiled for 5 hours, worked up in the usual manner, and 4-isopropylaminospiro[cyclohexane-l,9'-thioxanthene] is thus obtained; hydrobromide, M.P. 302; hydrogen malonate, MP. 179'.

Analogously, using the following starting compounds:

4-methyliminospiro[cyclohexane-1,9'-thioxanthene], 4-ethyliminospiro[cyclohexane-1,9'-thioxanthene] 4-n-propyliminospiro [cyclohexane-l ,9-thioxanthene] 4-n-butyliminospiro [cyclohexanel ,9'-thioxanthene] 4-isobutyliminospiro[cyclohexane-1,9-thioxanthene], 4-sec .-butyliminospiro [cyclohexanel,9'-thioxanthene] 4-tert.-butyliminospiro[cyclohexane-1,9'-thioxanthene1, 4-n-amyliminospiro [cyclohexane- 1,9 '-thioxanthene] 4-isoamyliminospiro [cyclohexane- 1 ,9 '-thioxanthene] 4-pentyl- (2) -iminospiro[cyclohexane-1,9'-thioxanthene] 4-pentyl- (3 )-iminospiro [cyclohexane- 1 ,9'-thioxanthene 1 4-neopentyliminospiro[cyclohexane-1,9'-thioxanthene], 4- 3 -Inethylbutyl- (2) l-iminospiro [cyclohexanel ,9

thioxanthene] 4- 2-methylbutyl-( l) ]-iminospiro[cyclohexane-1,9'-

thioxanthene] 13 4-tert.-amyliminospiro [cyclohexane-l,9'-thioxanthene] 4-n-hexyliminospiro[cyclohexane-l ,9'-thioxanthene] 4-isohexyliminospiro[cyclohexane-l,9'-thioxanthene] and 4-hexyl-(2) -iminospiro [cyclohcxane-1,9'-thioxanthene] the compounds set forth below are obtained, respectively,

4-mcthylaminospiro [cyclohexane- 1 ,9'-thioxanthene] hydrochloride, M.P. 279

4-ethylaminospiro [cyclohexane-l ,9'-thioxanthene] hydrobromide, M.P. 261;

4-np ropylam in os piro [cyclohexane-1,9'-thioxanthene] hydrobromide, M.P. 277

4n-butylaminospiro [cyclohexanel,9'-thioxanthene] 4-isobutylaminospiro [cyclohexane-l,9'-thioxanthene] 4-sec.-butylarninospiro [cyclohexane-l ,9-thioxanthene] 4-tert.-butylaminospiro [cyclohexane-l,9'-thioxanthene] 4 n-amyla mi nospiro [cyclohexanel,9'-thioxanthene 4-isoamylaminospiro[cyclohexane-1,9'-thioxanthene] 4-pentyl-( 2 -aminospiro [cyclohexane- 1 ,9'-thioxanthene] 4'pentyl-( 3 -aminospiro[cyclohexane- 1,9'-thioxanthene] 4-neopentylaminospiro [cyclohexane- 1 ,9'-thioxanthene] 4- [3-methylbutyl- 2) ]-arninospiro[cyclohexane-1,9'-

thioxanthene 1;

4 2-methylbutyl-( 1 ]-aminospiro [cyclohexane-l ,9-

thioxanthene] 4-tert.-amylaminospir0 [cyclohexanel ,9-thioxanthene] 4-n-hexylaminospiro [cyclohexane-l ,9'-thioxanthene] 4-isohexylaminospiro [cyclohexanel,9'-thioxanthene];

and

4-hexyl- 2 -aminospiro[cyclohexane-l ,9'-thioxanthene] (b) 2.6 g. of 4-isopropylaminospiro[cyclohexane-l,9- thioxanthene] is mixed with 20 ml. of formic acid and 5 ml. of 35% formaldehyde solution and heated to 60 for 3 hours, and thereafter to 100 for 5 hours. Subsequently, the reaction mixture is concentrated by evaporation, the residue is taken up in dilute sodium hydroxide solution, and extracted with ether. From the extract, 4-(N-methyl- N isopropylamino) spiro[cyclohexane l,9'-thioxantheme] is obtained; hydrobromide, M.P. 231.

Analogously, the following tertiary amines, or the associated hydrochlorides and hydrobromides, can be pro duced from the secondary amines synthesized according to d-dimethylarninospiro [cyclohexane- 1 ,9'-thioxanthene] hydrochloride, M.P. 270;

4- N-methyl-N-ethylamino) -spiro [cyclohexane- 1 9'- thioxanthene] hydrobromide, M.P. 228

4- (N-methyl-N-n-propylamino) -spiro [cyclohexanel ,9

thioxanthene], hydrochloride, M.P. 217

4- N-methyl-N-nbutyl amino) -spiro [cyclohexanel ,9-

thioxanthene] 4-( N-meth yl-N-isobutyl amino -s piro [cyclo hexanel ,9-

thioxanthene] 4- Nmethyl-N-sec.-butylamino) -spiro[cyclohexanel ,9-

thioxanthene] 4- N-methyl-N-terL-butylami no) -spiro cyclohexane- 1,9

thioxanthene];

4- N-methyl-N-n-amylamino) -spiro [cyclohexan e- 1,9-

thioxanthene] 4-(N-methyI-N-isoamylamino)-spiro [cyclohexane- 1,9-

thioxanthene];

4- [N-methyl-N-pentyl-(Z -amino] -spiro [cyclohexanel,9'-thioxanthene] 4- N-methyl-N-pentyl- (3 -amino] spiro [cyclohexanel,9'-thioxanthene];

4-(N-methyl-N-neopentylamino) -spir [cyclohexanel,9'-thioxanthene];

4- [N-methyl-N-( B-methyl -butyI- (2 -amino] -spiro [cyclohexane-l,9'-thioxanthene] 4-[N-rr1ethyl-N- 2-rnethyl)-butyl( l )-amino]spiro [cyclohexanel ,9'-thioxanthene] 4-(N-methy1-N-tert.-amylamino -spiro [cyclohexanel,9'-thioxanthene] 14 4-(N-methyl-N-n-hexylamino)-spiro[cyclohexane-1,9-

thioxanthene]; 4-(N-methyl-N-isohexylamino)-spiro[cyclohexane- 1,9-

thioxanthene]; and 4-[ N-methyl-N-hexyl-(Z -amino1-spiro [cyclohexanel,9'-thioxanthene] Example 5 10 g. of spiro[cyclohexane-1,9'-thioxanthen]-4-one is heated with 30 g. of isopropylamine in a bomb to 200 for 12 hours. Thereafter, the excess isopropylamine is evaporated, the reaction mixture is taken up in methanol, and hydrogenated in the presence of Raney nickel and methanolic KOH at 6 atmospheres and 60". After the absorption of 2 mols of hydrogen, the reaction mixture is vacuum-filtered from the catalyst, the methanol is removed, and the mixture taken up in water and chloroform. From the chloroform phase, 4-isopropylaminospiro[cyclohexane 1,9 thioxanthene] is obtained; hydrobromide, M.P. 302.

Example 6 (a) 2'-chlorospiro[cyclohexane-l,9'-thioxanthen] 4- one [M.P. 75; obtainable by oxidation of 2-chlorothioxanthene to 2-chlorothioxanthene sulfoxide (M.P. 12l- 122) and subsequent reactions by way of 9,9-bis(2- cyanoethyl)-2-chlorothioxanthene sulfoxide, 9,9 bis(2- cyanoethyl)-2-chlorothioxanthene, 2 chloro9,9-thioxanthenedipropionic acid (M.P. 240), the dimethyl ester of 2-chloro-9,9-thioxanthenedipropionic acid (M.P. 97), and the methyl ester of 2-chlorospiro[cyclohexane-l.9'- thioxanthen]-4-one-3-carboxylic acid (M.P. 142-143")] is reacted, analogously to Example 4(a), with ten times the amount of methylamine to 2'-chloroA-methyliminospiro [cyclohexane-l,9'-thioxanthene] which is hydrogenated in the crude condition to 2'-chloro-4-methylamiuospiro [cyclohexane-l,9' thioxanthene]; hydrochloride, M.P. 302; hydrogen malonate, M.P. 174475".

Analogously, the following compounds are obtained with ammonia or the corresponding primary amines:

2'-chlo ro-4-aminospiro [cyclohexanel ,9'-thioxanthene 2'-chloro-4-ethylaminospiro [cyclohexanel ,9'-thioxanthene],

2'-chloro 4-propylaminospiro[cyclohexane-l,9-thioxanthene] and 2'-chloro-4-isopropylaminospiro[cyclohexane-l,9'-thioxanthene] Produced from 2',7-dichlorospiro[cyclohexane-l,9"thioxanthen]-4-one are:

2',7'-dichloro-4-aminospiro [cyclohexane-l,9'-thioxanthene] 2',7'-dichloro-4-methylaminospiro [cyc1ohexane-1,9'-thioxanthene] 2',7'-dichloro-4-ethylaminospiro [cyclohexane-1,9-thioxanthene] 2',7'-dichloro-4-propylaminospiro[cyclohexane-l,9-

thioxanthene] 2,7'-dichloro-4-isopropylaminospiro[cyclohexane-l,9-

thioxanthene] (b) In accordance with the process described in Example 1(c), there is introduced from 2'-chloro-4-methylaminospiro{cyclohexane 1,9 thioxanthene] the compound 2'-chloro-4-dimethylaminospiro[cyclohexane 1,9- thioxanthene]; hydrochloride, M.P. 301-302".

Analogously, the following compounds are obtained from the secondary amines disclosed under (a):

2'-chloro-4-methylethylaminospiro[cyclohexane-1,9-

thioxanethene 1 2'-chloro-4-N-rnethyl-N-propylaminospiro [cyclohexanel,9'-thioxanthene 2'chloro-4-N-methyl-N-isopropylaminospiro [cyclohexane-l,9-thioxanthene],

2',7'-dichloro-4-dimethyl am inospiro [cyclohexane- 1,9

thioxanthene] 2',7 '-dichloro-4-methylethylaminospiro cyclohexane-l ,9

thioxa nthene] 2',7'-dichloro-4-N-methyl-N-p ropylaminospiro [cyclohexanel ,9'-thioxanthene and 2',7'-dichloro-4-N-methyl-N-isopropylaminospiro [cyclohexane-1,9'-thioxanthene].

Example 7 4.7 g. of 4acetamidospiro[cyclohexane-l,9'-thioxanthene] (M.P. 213; obtainable by acetylation of 4-aminospiro[cyclohexane-l,9-thioxanthene]) is boiled overnight with 1.2 g. of lithium aluminum hydride and 4 g. of anhydrous aluminum chloride in 200 ml. of absolute ether. Thereafter, the reaction mixture is decomposed by the addition of dilute hydrochloric acid, the ether is separated, the aqueous phase is mixed with tartaric acid,

poured into an excess of sodium hydroxide solution, and

extracted with chloroform. After the chloroform has been removed by evaporation, 4-ethylaminospiro[cyclohexane- 1,9-thioxanthene] is obtained; hydrobromide, M.P. 261 (from ethanol/ether).

Analogously, using as starting compounds:

d -propionylamidospiro [cyclohexane-1,9-thioxanthene] 4-methylacetamidospiro[cyclohexane-1,9-thioxanthene] and 4-methyl propionylamidospiro [cyclohexane- 1,9-th ioxanthene the following compounds are obtained, respectively:

4-propylaminospiro [cyclohexane-1,9-thioxanthene] hydrobromide, M.P. 277; hydrogen malonate, M.P. 168;

4- (N-ethyl-N-methylamino )-spiro [cyclohexanel ,9'-thioxanthene]; hydrobromide, M.P. 228; and

4-(N-methyl-N-propylamino)-spiro[cyclohexane-l,9'-

thioxanthene]; hydrochloride, M.P. 217.

Example 8 Example 9 A solution of 6 g. of 4ethylidenaminospiro[cyclohexane-I,9'-thioxanthene] (obtainable from the corresponding 4-amino compound by reaction with acetaldehyde) is hydrogenated in 150 ml. of methanol after the addition of 0.5 g. of platinum oxide, at room temperature and under normal pressure. After an amount of hydrogen corresponding to 1 mol has been absorbed, the reaction mixture is vacuum-filtered from the catalyst, acidified with dilute hydrochloric acid, and the methanol is removed under vacuum. The residual aqueous solution is made alkaline with sodium hydroxide solution and extracted with ether. After the ether extract has been dried and concentrated, 4-ethylaminospiro[cyclohexane 1,9- thioxanthene] is obtained; hydrobromide, M.P. 261.

Example 10 Approximately 13 g. of crude 4-methylpropylaminospiro[cyclohexene-(3) 1,9 thioxanthene] (obtainable from spiro[cyclohexane 1,9. thioxanthen1-4-one and methylpropylamine at 180) is dissolved in 200 ml. of methanol and hydrogenated, after the addition of 4 g. of Raney nickel at 6 atmospheres and 60. After removing the catalyst by vacuum-filtering, the methanol is distilled 16 off, up to a small remainder, and the hydrochloride of 4 methylpropylaminospiro[cyclohexane 1,9 thioxanthene], M.P. 217, is precipitated with ethereal hydrochloric acid. Free base, B1. 183l86/0.05 mm.

By hydrogenating the corresponding enamines, the following compounds are analogously obtained:

4-dimethylaminospiro[cyclohexane-1,9-thioxanthene] hydrochloride, M.P. 270

4-diethylaminospiro[cyclohexane-1,9 '-thioxanthene] 4-me thylethylatninos piro [cyclohexane- 1,9 '-thioxanthene] (hydrobromide, M.P. 228

4-methylisopropylaminospiro[cyclohexane-1,9-

thioxanthene] (hydrobromide, M.P. 231);

4-methylbutylaminospiro [cyclohexane- 1,9

thioxanthene];

4-methylisobutylaminospiro [cyclohexane-1,9'-

thioxanthene];

4-methyl-sec.-butylarninospiro [cyclohexane-l,9-

thioxanthene];

4-methyl-tert.-butylaminospiro [cyclohexane-1,9'-

thioxanthene] 4-methyl-n-amylaminospiro[cyclohexane-1,9'-

thioxanthene] 4-rnethylisoamylamin0spiro [cyclohexanel ,9-

thioxantbene] 4-methylpentyl-(2)-aminospiro[cyclohexane-1,9-

thioxanthene];

4methylpentyl (3 )aminospiro [cyclohexane- 1,9-

thioxanthene];

4-methylneopentylaminospiro [cyclohexanel ,9-

thioxanthene];

4-methyl- 3 -rnethylbutyl-(2) l-aminospiro cyclohexane- 1,9-thioxanthene];

4-methyl- 2-methylbutyl-( 1) ]-aminospiro [cyclohexane- 1 ,9-thioxanthene] 4-methyl-tert.-amylaminospiro [cyclohexane- 1 ,9-

thioxanthene] 4-methyl-n-hexylaminospiro [cyclohexane- 1,9-

thioxanthene] 4-methylisohexylaminospiro [cyclohexane- 1,9-

thioxanthene] and 4-methylhexyl- (2) -aminospiro cyclohexanel ,9-

thioxanthene] Example 1 1 11.2 g. of spiro[cyclohexene-(2)-1,9-thioxanthene1-4- one, 7.9 g. of N-methylpiperazine, and 50 ml. of tetrahydrofuran are shaken for 12 hours at in a bomb tube. After cooling, the reaction mixture is concentrated by evaporation, the thus-formed 4-(4-methylpiperazino)- spiro [cyclohexadiene-(2,4)-l,9'-thioxanthene] is dissolved in 200 ml. of methanol, and after the addition of 4 g. of Raney nickel, the reaction mixture is hydrogenated at 6 atmospheres and 60. After vacuum-filtering the catalyst, the reaction mixture is acidified with hydrochloric acid, and the methanol is distilled off, resulting in 4-(4-methylpiperazino) spiro[cyclohexane-l,9'-thioxanthene]; dihydrobromide, M.P. 300.

Analogously, the following compounds are produced by reacting the corresponding spiro[cyclohexene (2) thioxanthen]-4-ones with the corresponding cyclic amines and subsequent hydrogenation:

4-pyrrolidinospiro [cyclohexanel ,9'-thioxanthene] 4-piperidinospiro[cyclohexane-1,9-thioxanthene] 4-morpholinospiro[cyclohexane-1,9-thioxanthene] 4- 2-methylpyrrolidino) -spiro cyclohexane 1 ,9-

thioxanthene] 4- (3-methylpyrrolidino) -spiro[cycl0hexane- 1,9-

thioxanthene] 4-(Z-methylpiperidino)-spi.ro[cyclohexanc-1,9'-

thioxanthene] 4-(4-rnethylpiperidino)-spiro[cyclohexane-1,9-

thioxanthene];

4- (Z-ethylpiperidino )-spiro [cyclohexane- 1,9-

thioxanthene] 4- 4-ethylpiperidino)-spiro cyclohexane- 1 ,9-

thioxanthene] 2'-chloro-4-pyrrolidinospiro[cyclohexane-1,9-

thioxanthene] 2'-chloro-4-piperidinospiro [cyclohexane-l ,9-

thioxanthene] 2-chloro- 4-methylpiperazino -spiro [cyclohexanel ,9-

thioxanthene] 2',7 -dichloro-4-pyrrolidinospiro [cyclohexane-1,9-

thioxanthene] 2,7 -dichloro-4-piperidinospiro [cyclohexane-1,9-

thioxanthene]; and

2,7-dichloro-4- (4-methylpiperazino -spiro [cyclohexane- 1 ,9-thioxanthene] Example 12 A solution of 7.2 g. of 4-chlorospiro[cyclohexane-1,9- thioxanthene] (obtainable by reducing spiro[cyclohexane- 1,9'-thioxanthen]-4-one with LiAlH, to spiro[cyclohexane-l,9-thioxanthen]-4-ol and reaction of the latter held with SOCI and 3.6 g. of isopropylamine in 50 ml. of toluene is boiled until no further precipitation of isopropylamine hydrochloride occurs. The reaction mixture is cooled, filtered, the filtrate extracted with dilute hydrochloric acid, and the largest portion of the organic solvent is removed under vacuum. The remaining aqueous solution is made alkaline with solution of sodium hydroxide and extracted with ether. From the ether extract, 4 isopropylaminospiro[cyclohexane-1,9'-thioxanthene] is obtained; hydrogen malonate, M.P. 179.

Analogously, from the corresponding 4-chlorospiro [cyclohexane-l,9"-thioxanthenes], the following compounds are produced by reaction with corresponding amines: 4 methylaminospiro[cyclohexane 1,9 thioxanthene]; hydrochloride, M.P. 279; and 2' chloro-4- methylaminospiro[cyclohexane 1,9 thioxanthene]; hydrochloride, M.P. 302".

Example 13 11 g. of spiro[cyclohexane-l,9-thioxanthen]-4-o1 is dissolved in 40 m1. of isopropylamine, and the solution is shaken in a bomb tube for 15 hours at 160, after the addition of 2 g. of Raney nickel. After filtering off the catalyst, the excess isopropylamine is distilled olT, the reaction mixture, after adding water thereto, is extracted with ether, and the ether layer is thoroughly washed with water. From the ether extract, 4-isopropylaminospiro[cyclohexane-1,9-thioxanthene] is obtained; hydrobromide, M.P. 302.

Analogously, by reacting the corresponding 4-hydroxyspiro[cyclohexane 1,9 thioxanthenes] with the corresponding primary or secondary amines, the following compounds are obtained:

4-methylaminospiro [cyclohexanel,9-thioxanthene] hydrochloride, M.P. 279;

4-ethylaminospiro[cyclohexane-1,9-thioxanthene];

hydrobromide, M.P. 261;

4-n-propylaminospiro [cyclohexane-l ,9-thioxanthene];

hydrobromide, M.P. 277

4-n-butylaminospiro [cyclohexane-l,9-thioxanthene];

4-sec.-butylaminospiro [cyclohexanel ,9-thioxanthene] 4-dimethylaminospiro [cyclohexane-1,9'-thioxanthene] hydrochloride, M.P. 270;

4-diethylaminospiro [cyclohexanel ,9 thioxanthene] 4-methylethylaminospiro[cyclohexane-1,9 -thioxanthene]; hydrobromide, M.P. 228;

4-methylpropylaminospiro[cyclohexane-1,9-thioxanthene]; hydrochloride, M.P. 217;

4-methylisopropylaminospiro[cyclohexane-1,9-

thioxanthene] 4-pyrrolidinospiro[cyclohexane-1,9-thioxanthene] 4-piperidinospiro[cyclohexane-1,9-thioxanthene] 4-morpholinospiro[cyclohexane-1,9-thioxanthene] and 4- (4-methylpiperazino -spiro [cyclohexanel,9-thioxanthene]; dihydrochloride, M.P. 287.

Example 14 (a) 10 g. of crude 4-benzylaminospiro[cyclohexane-l, 9-thioxanthene] (obtainable from spiro[cyclohexane-l, 9'-thioxanthen]-4-one by reaction with benzylamine to 4- benzyliminospiro [cyclohexanel ,9-thioxanthene] and subsequent reduction with LiAlI-L) is dissolved in 200 ml. of methanol, and hydrogenated after the addition of 6 g. of Raney nickel at 6070 and 100-150 atmospheres, thus removing the benzyl residue. 4-aminospiro[cyclohexanel,9-thioxanthene] is obtained; hydrochloride, M.P. 310.

(b) Hydrogenation of 4benzyliminospiro[cyclohexane-1,9-thioxanthene] in methanol on Raney nickel results in 4 aminospiro[cyclohexane-1,9-thioxanthene]; hydrochloride, M.P. 310".

Example 15 2.5 g. of crude 4-benzylaminospiro[cyclohexane-1,9- thioxanthene] is dissolved in 50 ml. of methanol and hydrogenated after the addition of 200 mg. of 5% palladium charcoal at room temperature and normal pressure until the reaction is terminated. The reaction mixture is filtered ofl from the catalyst, acidified with dilute hydrochloric acid, and the methanol is removed under vacuum. The residual aqueous solution is made alkaline with solution of sodium hydroxide and extracted with ether. From the ether extract, after the ether has been dried and removed, 4-aminospiro[cyclohexane 1,9 thioxanthene] is produced; hydrochloride, M.P. 310 (from ethanol/ether).

Example 16 8.2 g. of 4-phthalimidospiro[cyclohexane-l,9'-thioxanthene] (obtainable from 4-chlorospiro[cyclohexane-l,9- thioxanthene] by reaction with potassium phthalimide) and 1.3 g. of hydrazine hydrate are heated in an ethanolic suspension for 4 hours on a steam bath. Thereafter, 10 ml. of concentrated hydrochloric acid is added, and the phthalic acid hydrazide is filtered oil in the hot state after 30 minutes. The filtrate is concentrated by evaporation, thus obtaining 4-aminospiro[cyclohexane- 1,9-thioxanthene]; hydrochloride, M.P. 310.

Example 17 One gram of 4-phthalimidospiro[cyclohexane-l,9- thioxanthene] is boiled with 10 ml. of concentrated hydrochloric acid for 6 hours. The largest portion of the hydrochloric acid is distilled off, the reaction mixture made alkaline with solution of sodium hydroxide, and the base is extracted with ether. After drying the ethereal solution, ethereal hydrochloric acid is added, and the 4- aminospiro[cyclohexane 1,9 thioxanthene] hydrochloride is filtered ofi; M.P. 310 (from ethanol/ether).

Example 18 12 g. of 4-chlor0spiro[cyclohexane-l,9-thioxanthene] is dissolved in 60 ml. of absolute tetrahydrofuran. Several milliliters of this solution are allowed to flow into a suspension of 1.1 g. of magnesium filings in 10 ml. of absolute tetrahydrofuran. After the addition of a small amount of iodine, the mixture is heated to 5060 until the reaction is initiated. Then, the remainder of the solution is gradually added dropwise to the reaction mixture, under a continuous supply of heat, and then the reaction mixture is stirred at 50-60 until a large portion of the magnesium has been consumed. The mixture is thereafter cooled to -10", and at this temperature a solution of 2 g. of O-methylhydroxylamine in absolute tetrahydrofuran is added dropwise. Then, the reaction mixture is agitated further for 2 hours at 10 and for 2 hours at room temperature. The mixture is decomposed by the addition of aqueous hydrochloric acid, the largest portion of the tetrahydrofuran is removed, the mixture washed with ether, the acidic aqueous phase made alkaline with sodium hydroxide solution, and extracted with ether. The alkaline ether extract yields 4-aminospiro[cyclohexane- 1,9'-thioxanthene]; hydrochloride, M.P. 310.

Analogously, the following compounds are obtained with O,N-dimethyland O,N,N-trimethylhydroxylamine:

4-methylaminospiro[cyclohexane-1,9'-thioxanthene];

hydrochloride, M.P. 279; and

4-dimethylaminospiro[cyclohexane-1,9'-thioxanthene] hydrochloride, M.P. 270".

Example 19 24.8 g. of dimethylamino-4,4-diphenylcyclohexane hydrochloride is mixed with a mixture of 13 g. of sulfur dichloride and 17.4 g. of anhydrous aluminum chloride in 540 ml. of carbon disulfide, and thereafter agitated for 13 hours at 30. Then, the reaction mixture is poured on ice containing hydrochloric acid, the organic layer is separated. and the aqueous layer is mixed with tartaric acid. Thereafter, sodium hydroxide solution is added, and the aqueous layer is extracted with ether, thus obtaining 4 dimethylaminospiro[cyclohexane-1,9'-lhioxanthenel: hydrochloride, M.P. 270.

Analogously, using as starting compounds N-methyl-N-ethylamino-4,4-diphenylcyclohexane hydrochloride and N-methyl-N-n-propylamino-4,4-diphenylcyclohexane hydrochloride,

the following compounds are obtained: 4-(N-methyl-N-ethylamino)-spiro[cyclohexane-l,9'-

thioxanthene]; hydrobromide, M.P. 228; and 4-(N-methyl-N-n-propylamino)-spiro[cyclohexane-1,9'- thioxanthene], hydrochloride, M.P. 217.

The following examples relate to pharmaceutical preparations of the novel compounds:

Example A.Tablets Each tablet contains:

Mg. 4 methylaminospirotcyclohexane-1,9-thioxanthene] hydrochloride 2 Lactose 70 Corn starch 26 Magnesium stearate 2 Example B.Coated tablets Each tablet contains:

Mg. 4 dimethylaminospiro[cyclohexane 1,9 thioxanthene] hydrochloride 3 Lactose 80 Potato starch Talc 2 The coating (150 mg.) is a conventional mixture of corn starch, sugar, talc, and tragacanth.

Example C.Injection solution A solution of 2 kg. of 4-methylaminospiro[cyclohexane-1,9'-thioxanthene] hydrochloride in 998 kg. of distilled water is prepared and filled into ampoules in such a manner that each arnpoule contains 2 mg. of the abovementioned hydrochloride.

Example D.-Syrup A mixture of 2'-chloro 4 methylaminospirotcyclohexane-1,9-

thioxanthene] hydrochloride 0.2 Glycerin (twice distilled) 7.5 Cane sugar 56.0 Methyl-p-hydroxybenzoate 0.07 n-Propyl-p-hydroxybenzoate 0.03 Ethanol 10.0

Fruit flavoring as desired is prepared and mixed with distilled water in such a manner that the volume of the entire mixture is l. One dosage unit (5 ml.) contains 10 mg. of active substance.

in place of the salts of the active substances disclosed in Examples A-D, it is also possible to employ other physiologically compatible acid addition salts of these compounds, the corresponding free bases, or other compounds of general Formula I, as Well as the physiological 1y acceptable acid addition salts and quaternary ammonium salts thereof.

The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

l. A 4-aminospiro[cyclohexanel,9'-thioxanthene] of the formula wherein R is H or alkyl of 16 carbon atoms and R is H or alkyl of 1-3 carbon atoms, or R and R collectively with the nitrogen atom connecting them, are morpholino or pyrrolidino, piperidino or piperazino, the latter three groups being unsubstituted or substituted by methyl or ethyl; and R and R each are H or Cl, including the physiologically acceptable acid addition and quaternary ammonium salts thereof.

2. A compound of claim 1 wherein R and R are H or alkyl as defined therein.

3. A compound of claim 1 wherein R is H.

4. A compound of claim 1 wherein R is H.

5. A compound of claim 1 wherein R, is alkyl of 1-4 carbon atoms.

6. A compound of claim 2 wherein R, is H.

7. A compound of claim 6 wherein R is H.

8. A compound of claim 6 wherein R is Cl.

9. A compound of claim 1 as a physiologically acceptable acid addition salt.

10. A compound of claim 9 wherein the acid addition salt is the hydrochloride.

11. A compound of claim 1, 4-aminospiro[cyclohexane- 1,9'-thioxanthene].

12. A compound of claim 1, 4-methylaminospiro[cyclohexane-1,9-thioxanthenel.

13. A compound of claim 1, 4-ethylaminospiro[cyclohexane-1,9'-thioxanthene1.

14. A compound of claim 1, 4-n-propylaminospiro[cyclohexane-1,9-thioxanthenel 15. A compound of claim 1, 4-isopropylaminospiro[cyclohexane-l,9'-thioxanthene1.

16. A compound of claim 1, 4-dimethylaminospiro[cyclohexane- 1 ,9'-thioxanthene] 17. A compound of claim 1, 4-(N-methyl-N-ethylamino)-spiro[cyclohexane-1,9'-thioxanthene].

18. A compound of claim 1, 4-(N-methyl-N-n-propylamino)-spiro[cyclohexane- 1 ,9-thioxanthene].

19. A compound of claim 1, 4-(N-methyl-N-isopropy1- amino) -spiro[cyclohexane- 1 ,9'-thioxanthene].

20. A compound of claim 1, 4-(4-methylpiperazino)- spiro[cyc1ohexane-l,9-thioxanthene].

21 21. A compound of claim 1, 4-methylamino-2-chlorospiro[cyclohexane-l,9-thioxanthene].

22. A compound of claim 1, 4-dimethylamino-2'-chlorospiro[cycloheXane-1,9'-thioxanthene].

23. A compound of claim 1, N,N,N-trimethyl-N-spiro 5 [cyclohexane 1,9 thioxanthen]-yl-(4)-ammonium bromide.

24. A compound as defined by claim 1 wherein R is alkyl of 1-6 carbon atoms and R is alkyl of 1-3 carbon atoms.

25. A compound as defined by claim 24 wherein R is alkyl of 1-4 carbon atoms.

26. A compound as defined by claim 24 wherein R is methyl.

27. A compound as defined by claim 24 wherein R is methyl.

References Cited UNITED STATES PATENTS 3,048,595 8/1962 Zirkle 260-293.4

HENRY R. JILES, Primary Examiner C. S. JAISLE, Assistant Examiner US. Cl. X.R.

260-247, 247.], 268 R, 293.57, 293.72, 295 T, 295.5 T, 326.8, 326.84, 328; 424-248, 250, 266, 267, 274, 275 

